The present invention relates to a process for producing alanylglutamine and a novel N-(2-substituted) propionylglutamine compound which is an intermediate for the alanylglutamine. Further, the present invention relates to a process for producing the N-(2-substituted) propionylglutamine and N-(2-D-bromo)propionyl-L-glutamine, which is a known intermediate for the L-alanyl-L-glutamine. L-alanyl-L-glutamine has higher stability and higher water-solubility than L-glutamine, and is used as the component of the infusion solution.
For the production of alanylglutamine, there have heretofore been known three types of methods (1), (2) and (3): (1) methods of using a protecting group, for example, the method which comprising condensing an N-benzyloxycarbonylalanine (hereinafter referred to as a "Z-alanine") with a protected glutamine in the presence of dicyclohexylcarbodiimide (DCC), and removing the protecting group from the intermediate compound [Bull. Chem. Soc. Jpn., 34, 739 (1961); Bull. Chem. Soc. Jpn., 35, 1966 (1962)]; the method which comprising condensing a Z-alanine with a protected .gamma.-methyl glutamate in the presence of DCC, removing the protecting group from the intermediate compound and further reacting the deprotected product with ammonia [Bull. Chem. Soc. Jpn., 37, 200 (1964)]; and the method which reacting an active ester of a Z-alanine with a non-protected glutamine and removing the protecting group from the intermediate compound (European Patent No. 311,057); (2) the method for producing alanylglutamine via an N-carboxyl anhydride (German Patent No. 3,206,784); and (3) the method using 2-bromopropionyl chloride as a starting compound via an intermediate compound, 2-bromopropionylglutamine (Hoppe-Seyler's Z. Physiol. Chem., 105, 58 (1919)).
The methods (1) using a protecting group need the step of removing the protecting group from the intermediate compound and the operation for the step is complicated. Therefore, the methods (1) yield alanylglutamine at higher cost. The method (2) uses an N-carboxyl anhydride of a alanine without involving a protecting group. However, by-products such as tripeptides are considerably produced and the yield of the intended product is lower. In addition, it is difficult to purify the intended product. In the method (3), since an acid chloride having a high reactivity with water is added to an aqueous solution of glutamine for the reaction of 2-bromopropionyl chloride with glutamine, the method involves hydrolysis of the acid chloride. Therefore, the method (3) yields by-products and the yield of the intended product is low. Since the produced 2-bromopropionylglutamine is purified by extraction with an organic solvent, the yield and optical purity of the product are low. In addition, in the method (3), since the ammonolysis of 2-bromopropionylglutamine is carried out at a higher temperature, by-products are considerably produced and the optical purity of the produced alanylglutamine is often low.